EP0039920B1 - Triazaloquinoxalin-1,4-diones - Google Patents

Triazaloquinoxalin-1,4-diones Download PDF

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Publication number
EP0039920B1
EP0039920B1 EP81103498A EP81103498A EP0039920B1 EP 0039920 B1 EP0039920 B1 EP 0039920B1 EP 81103498 A EP81103498 A EP 81103498A EP 81103498 A EP81103498 A EP 81103498A EP 0039920 B1 EP0039920 B1 EP 0039920B1
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hydrogen
alkyl
methyl
compound according
carb
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EP0039920A2 (en
EP0039920A3 (en
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Richard E. Brown
Vasil St. Georgiev
Philip Kropp
Bernard Loev
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USV Pharmaceutical Corp
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USV Pharmaceutical Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to new anti-allergic agents and more particularly to certain new triazolo- quinoxalin-1,4-diones possessing useful anti-allergic activity of particular use in the treatment of asthma.
  • the traizoloquinoxalin-1,4-diones of this invention are new compounds not previously described in the literature and show significant anti-allergy activity as shown in standard tests used for evaluation of such activity. These compounds show particularly significant activity in inhibiting formation of a wheal when screened according to the Rat Passive Cutaneous Anaphylaxis Screen [I. Mota, Life Science, 7, 465 (1963) and Z. Ovary, et al., Proceedings of Society of Experimental Biology and Medicine, 81, 584 (1952)].
  • the present new compounds also demonstrate potent activity as inhibitors of histamine release from passively sensitized Rat Mast cells according to the procedure described by E. Kusner, et al., Journal of Pharmacology and Therapeutics. Thus, the present new compounds are especially useful in the treatment of asthma and other allergic reactions.
  • the particularly preferred compounds of the invention are those in which X is oxygen, that is the triazoloquinoxalin-1,4-diones.
  • the new compounds of the invention can be prepared by art-recognized procedures from known starting compounds. For example, the following procedure can be employed for compounds of formula I.
  • the sulfur analogs and compounds of Formula II can be prepared by analogous procedures.
  • Substituents R, to R 4 can be added after formation of the basic ring structures by known substitution reactions, or by conversion of substituents such as reduction of nitro to form amino.
  • the substitution reactions mentioned include, for example, alkylation and acylation by known procedures.
  • heterocyclic compounds Using the procedures described, a wide variety of heterocyclic compounds can be prepared as follows:
  • the present new heterocyclic compounds are therapeutically useful as such or can be employed in the form of salts in view of their basic nature.
  • these compounds form salts with a wide variety of acids, inorganic and organic, including therapeutically-acceptable acids.
  • the salts with therapeutically-acceptable acids are, of course, useful in the preparation of formulations where water solubility is desired.
  • the salts with therapeutically-unacceptable acids are particularly useful in the isolation and purification of the present new compounds. Therefore, all acid salts of the present new compounds are contemplated by the present invention.
  • the pharmaceutically-acceptable acid addition salts are of particular value in therapy. These include salts of mineral acids such as hydrochloric, hydroiodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, as well as salts of organic acids such as tartaric, acetic, citric, malic, benzoic, glycollic, gluconic, succinic, aryl-sulfonic, e.g., p-toluenesulfonic acids.
  • the parma- ceutically-unacceptable acid addition salts while not useful for therapy, are valuable for isolation and purification of the new substances. Further, they are useful for the preparation of pharmaceutically-acceptable salts.
  • the more common salts include those formed with hydrofluoric and perchloric acids.
  • Hydrofluoride salts are particularly useful for the preparation of the pharmaceutically-acceptable salts, e.g., the hydrochlorides, by solution in hydrochloric acid and crystallization of the hydrochloride salt formed.
  • the perchloric acid salts are useful for purification and crystallization of the new products.
  • the present new heterocyclic compounds are particularly useful as anti-allergy agents, acting via inhibition of mediator release. These compounds are active orally in the passive cutaneous anaphylaxis (PCA) screen; and/or inhibit histamine release from passively sensitized rat mast cells.
  • PCA passive cutaneous anaphylaxis
  • the therapeutic agents of this invention may be administered alone or in combination with pharmaceutically-acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice.
  • they may be adminstered orally or in the form of tablets or capsules containing such excipients as starch, milk sugar, certain types of clay and so forth.
  • They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be injected parentally, that is, intramuscularly, intravenously or subcutaneously.
  • parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.
  • the physician will determine the dosage of the present therapeutic agents which will be most suitable and it will vary with the form of administration and the particular compound chosen, and furthermose, it will vary with the particular patient under treatment. He will generally wish to initiate treatment with small dosages substantially less than the optimum dose of the compound and increase the dosage by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally.
  • the compounds are useful in the same manner as other anti-allergy agents and the dosage level is of the same order of magnitude as is generally employed with these other therapeutic agents.
  • the therapeutic dosage will generally be from 10 to 750 milligrams per day and higher although it may be administered in several different dosage units. Tablets containing from 10 to 250 mg. of active agent are particularly useful.
  • the intermediate carbazate compounds which, on ring closure, form the new therapeutic agents of this invention are compounds which are represented by the formulae: wherein R,, R 2 , R 3 , R 4 and X and are-as hereinbefore described; R 5 is alkyl, preferably lower alkyl and Z forms a pyridine ring with the two carbon atoms to which it is attached.
  • the new carbazate intermediates are prepared by art-recognized procedures as described herein.
  • the intermediates also possess anti-allergic activity.
  • Example 3 15 g. of the product of Paragraph C, Example 3 was added with stirring to Dowtherm A (200 ml.) at 230°C. The reaction mixture was kept at this temperature until cyclization was completed (usually less than 20 minutes at this or higher temperature).
  • reaction mixture Upon completion of cyclization, the reaction mixture was cooled, filtered, and the solid washed well with ethanol and methylene dichloride.
  • the compounds of this invention are useful anti-allergic agents.
  • exemplary of the present new compounds is 6-methylpyrido(2,3-e)(1,2,4)triazolo(4,3-a)pyrazine-1,4-(2H,5H)dione which reduced wheal formation by 53% at 25 mg./kg. (p.o.) when screened according to the Rat Passive Cutaneous Anaphylaxis Screen as described by I. Mota, Life Sciences, 7, 465 (1963) and Z. Ovary, et al., Proceedings of Society of Experimental Biology and Medicine, 81, 584 (1952).
  • the said compound showed an I 50 of 9.0 ⁇ M in inhibition of histamine release from passively sensitized rat mast cells according to the procedure described by E. Kusner, et al., Journal of Pharmacology by Experimental Therapeutics.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Description

  • This invention relates to new anti-allergic agents and more particularly to certain new triazolo- quinoxalin-1,4-diones possessing useful anti-allergic activity of particular use in the treatment of asthma.
  • The traizoloquinoxalin-1,4-diones of this invention are new compounds not previously described in the literature and show significant anti-allergy activity as shown in standard tests used for evaluation of such activity. These compounds show particularly significant activity in inhibiting formation of a wheal when screened according to the Rat Passive Cutaneous Anaphylaxis Screen [I. Mota, Life Science, 7, 465 (1963) and Z. Ovary, et al., Proceedings of Society of Experimental Biology and Medicine, 81, 584 (1952)]. The present new compounds also demonstrate potent activity as inhibitors of histamine release from passively sensitized Rat Mast cells according to the procedure described by E. Kusner, et al., Journal of Pharmacology and Therapeutics. Thus, the present new compounds are especially useful in the treatment of asthma and other allergic reactions.
  • The new compounds of this invention are of the following formulae:
    Figure imgb0001
    wherein,
    • X is S or 0; each of R1 and R2 is hydrogen, C1―C10 alkyl, C2―C10 alkenyl, C2―C10 alkynyl, cyclo C3―C10 alkyl, C6―C10 aryl, C6―C10 ar C1―C10 alkyl, sulfonamido, halogen, C1―C10 alkoxy, C2―C10 alkenyloxy, C2―C10 alkynyloxy, cyano, hydroxy, nitro, amino, C1―C10 alkylamino, C1―C10 alkanoylamino, carb C1―C10 alkoxyamino, methansulfonyl, carboxy, carb C1―C10 alkoxy, trihalomethyl, or taken together, methylenedioxy;
    • each of R3 and R4 is hydrogen, C1―C10 alkyl, C6―C10 aryl, C2-5-alkanoyl, benzoyl, C6―C10 ar C1―C10 alkyl, cyclo C3―C10 alkyl, cyclo C3―C10 alkyl CH2―, or carb C1―C10 alkoxy; and the acid addition salts thereof.
  • The preferred compounds are of the formula
    Figure imgb0002
    wherein
    • each of R1 and R2 is hydrogen, C1―C10 alkyl, C2―C10 alkenyl, C2―C10 alkynyl, cyclo C3―C10 alkyl, C6―C10 aryl, C6―C10 ar C1―C10 alkyl, sulfonamido, halogen, C1―C10 alkoxy, C2―C10 alkenyloxy, C2―C10 alkynyloxy, cyano, hydroxy, nitro, amino, C1―C10 alkylamino, C1―C10 alkanoylamino, carb C1―C10 alkoxyamino, methanesulfonyl, carboxy, carb C1―C10 alkoxy, trihalomethyl, or taken together, methylenedioxy; and
    • each of R3 and R4 is hydrogen, C1―C10 alkyl, C6―C10 aryl, C2-5 alkanoyl, benzoyl, C6―C10 ar C1―C10 alkyl, cyclo C3―C10 alkyl, cyclo C3―C10 alkyl CH2―, or carb C1―C10 alkoxy;

    and acid addition salts thereof.
  • The particularly preferred compounds of the invention are those in which X is oxygen, that is the triazoloquinoxalin-1,4-diones.
  • The new compounds of the invention can be prepared by art-recognized procedures from known starting compounds. For example, the following procedure can be employed for compounds of formula I.
    Figure imgb0003
    The sulfur analogs and compounds of Formula II can be prepared by analogous procedures.
  • Substituents R, to R4 can be added after formation of the basic ring structures by known substitution reactions, or by conversion of substituents such as reduction of nitro to form amino. The substitution reactions mentioned include, for example, alkylation and acylation by known procedures.
  • Substituents on the present new compounds which are reactive and could interfere with ring closure reactions are best introduced by subsequent reactions known to the art such as reduction of nitro to amino, or hydrolysis of cyano to carboxamide or carboxy groups; alternatively, such reactive groups can be protected as by, for example, acylation of an amino group, followed by hydrolysis after ring closure.
  • Using the procedures described, a wide variety of heterocyclic compounds can be prepared as follows:
    Figure imgb0004
    Figure imgb0005
  • The present new heterocyclic compounds are therapeutically useful as such or can be employed in the form of salts in view of their basic nature. Thus, these compounds form salts with a wide variety of acids, inorganic and organic, including therapeutically-acceptable acids. The salts with therapeutically-acceptable acids are, of course, useful in the preparation of formulations where water solubility is desired. The salts with therapeutically-unacceptable acids are particularly useful in the isolation and purification of the present new compounds. Therefore, all acid salts of the present new compounds are contemplated by the present invention.
  • The pharmaceutically-acceptable acid addition salts are of particular value in therapy. These include salts of mineral acids such as hydrochloric, hydroiodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, as well as salts of organic acids such as tartaric, acetic, citric, malic, benzoic, glycollic, gluconic, succinic, aryl-sulfonic, e.g., p-toluenesulfonic acids. The parma- ceutically-unacceptable acid addition salts, while not useful for therapy, are valuable for isolation and purification of the new substances. Further, they are useful for the preparation of pharmaceutically-acceptable salts. Of this group, the more common salts include those formed with hydrofluoric and perchloric acids. Hydrofluoride salts are particularly useful for the preparation of the pharmaceutically-acceptable salts, e.g., the hydrochlorides, by solution in hydrochloric acid and crystallization of the hydrochloride salt formed. The perchloric acid salts are useful for purification and crystallization of the new products.
  • As therapeutic agents, the present new heterocyclic compounds are particularly useful as anti-allergy agents, acting via inhibition of mediator release. These compounds are active orally in the passive cutaneous anaphylaxis (PCA) screen; and/or inhibit histamine release from passively sensitized rat mast cells.
  • The therapeutic agents of this invention may be administered alone or in combination with pharmaceutically-acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, they may be adminstered orally or in the form of tablets or capsules containing such excipients as starch, milk sugar, certain types of clay and so forth. They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be injected parentally, that is, intramuscularly, intravenously or subcutaneously. For parenteral administration, they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.
  • The physician will determine the dosage of the present therapeutic agents which will be most suitable and it will vary with the form of administration and the particular compound chosen, and furthermose, it will vary with the particular patient under treatment. He will generally wish to initiate treatment with small dosages substantially less than the optimum dose of the compound and increase the dosage by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. The compounds are useful in the same manner as other anti-allergy agents and the dosage level is of the same order of magnitude as is generally employed with these other therapeutic agents. The therapeutic dosage will generally be from 10 to 750 milligrams per day and higher although it may be administered in several different dosage units. Tablets containing from 10 to 250 mg. of active agent are particularly useful.
  • The intermediate carbazate compounds which, on ring closure, form the new therapeutic agents of this invention are compounds which are represented by the formulae:
    Figure imgb0006
    wherein R,, R2, R3, R4 and X and are-as hereinbefore described; R5 is alkyl, preferably lower alkyl and Z forms a pyridine ring with the two carbon atoms to which it is attached.
  • The new carbazate intermediates are prepared by art-recognized procedures as described herein. The intermediates also possess anti-allergic activity.
  • The following examples further illustrate the invention.
    • Example 1 5-Methyl-pyrido-(2,3-e)(1,2,4)triazolo(4,3-a)pyrazine-1,4-(2H,5H)dione
  • Figure imgb0007
  • A mixture of 7.5 g of 2-chloro-4-methyl-pyrido(2,3-b)pyrazine-3-one, and 4 g. of methyl carbazate in 200 ml of Dowtherm A was stirred and heated at 80°C. for 1 hour and then at 230°C for 20 minutes.
  • It was then cooled and filtered. The crude product was crystallized twice from acetic acid - H20 to give the title compound in pure form, m.p.>300°C.
    • Example 2 2-Acetyl-5-methyl-pyrido(2,3-e)(1,2,4)triazolo(4,3-a)pyrazine-1,4-(2H,5H)dione
  • Figure imgb0008
  • A mixture of 1.8 g of 5-methyl-pyridio(2,3-e)(1,2,4)-triazolo(4,3-a)pyrazine-1,4-(2H,5H)dione in 25 ml. of acetic anhydride and 50 ml. of acetic acid was stirred and refluxed for 5 hours.
  • The mixture was cooled, filtered, and the product was washed with water, dried and crystallized from acetic acid-ether, m.p. 298-300°C.
    • Example 3 A. 1-Methylquinoxaline-2,3-dione
  • To a solution of 31 g. (0.36 m.) of oxylachloride in 50 ml. o-dichlorobenzene at 60° is added dropwise with stirring a solution of 31.3 g (0.256 m.) N-methyl-o-phenylene-diamine in 150 ml. of o-dichlorobenzene. The mixture is then heated over 1 hour to 160°C. and cooled to 20°C. The precipitated product is filtered, washed and dried, yield 82%, m.p. 277-286°C. It may be purified by recrystallization from methanol, m.p. 286-289°C.
    • B. 3-Chloro-1-methyl-1 H-quinoxalin-2-one
  • A mixture of 56.1 g. (0.32 m.) of 1,4-dihydro-1-methylquinoxalin-2,3-dione, 10 mi. of DMF, 50 ml. (0.67 m.) of thionyl chloride and 1 I. of toluene was refluxed for 1 hour, cooled, and stripped, finally under high vacuum to a crude dark solid, m.p. 124-130°C. of sufficient purity to use in the next step.
    • C. Ethyl-3-(1-methyl-2-oxo(2H)quinoxalin-3-yl)carbazate
  • A solution of 152 g. (0.78 m.) of 3-chloro-1-methyl-1 H-quinoxalin-2-one, 116g. (1.1 m.) of ethyl carbazate and 1 I. of acetonitrile is refluxed for 16 hours. The mixture is cooled to 9°C. and the product collected by filtration and used directly for cyclization.
  • In the same manner, the following carbazate compound are obtained:
    • Ethyl-3-(2-oxo(2H)quinoxalin-3-yl)carbazate
    • Ethyl-3-( 1-phenyl-2-oxo(2H)quinoxalin-3-yl)carbazate
    • Ethyl-3-(1,6-dimethyl-2-ono(2H)quinoxalin-3-yl)carbazate
    • Ethyl-3-(1,7-dimethyl-2-oxo(2H)quinoxalin-3-yl)carbazate
    • Ethyl-3-( 1,8-dimethyl-2-oxo(2H)quinoxalin-3-yl)carbazate
    • Ethyl-3-( 1-methyl-6-methoxy-2-oxo(2H)quinoxalin-3-yl)carbazate
    • Ethyl-3-( 1-methyl-6-trifluoromethyl-2-oxo(2H)quinoxalin-3-yl)carbazate
    • Ethyl-3-( 1-methyl-6,7-dimethoxy-2-oxo(2H)quinoxalin-3-yl)carbazate
    • Ethyl-3-( 1-methyl-8-chloro-2-oxo(2H)quinoxalin-3-yl)carbazate
    • Ethyl-3-(1-methyl-6-carbomethyl-2-,oxo(2H)quinoxalin-3-yl)carbazate
    D. 1-0xo-5-methyl-1 H,4H(1,2,4)triazolo(4,3-a)quinoxalin-4-one
  • 100 g. of the product of Paragraph C is heated under nitrogen with constant stirring to 200-260°C, for 30 minutes. After cooling, the yellow solid is finely powdered and extracted with 2 I. of hot acetonitrile. The insoluble material, m.p. 300°C., is analytically pure, but can be recrystallized from dimethylsulfoxide.
  • In the same manner, the following products are obtained:
    • 1-0xo-1 H,4H(1,2,4)triazolo(4,3-a)quinoxalin-4-one
    • 1-Oxo-5-phenyl-1 H,4H(1,2,4)triazolo(4,3-a)quinoxalin-4-one
    • 1-Oxo-5,8-dimethyl-1 H,4H(1,2,4)triazolo(4,3-a)quinoxalin-4-one
    • 1-Oxo-5,7-dimethyl-1 H,4H(1,2,4)triazolo(4,3-a)qu inoxalin-4-one
    • 1-Oxo-5,6-dimethyl-1 H,4H(1,2,4)triazolo(4,3-a)quinoxalin-4-one
    • 1-Oxo-5,7,8-trimethyl-1 H,4H(1,2,4)triazolo(4,3-a)quinoxalin-4-one
    • 1-Oxo-5-methyl-8-methoxy-1 H,4H(1,2,4)triazolo(4,3-a)quinoxalin-4-one
    • 1-Oxo-5-methyl-8-trifluoromethyl-1 H,4H(1,2,4)triazolo(4,3-a)quinoxalin-4-one
    • 1 -Oxo-5-methyl-7,8-dimethoxy-1 H,4H(1,2,4)triazolo(4,3-a)quinoline-4-one
    • 1-Oxo-5-methyl-6-chloro-1 H,4H(1,2,4)triazolo(4,3-a)quinoxalin-4-one
    • 1-Oxo-5-methyl-8-carbomethoxy-1 H,4H(1,2,4)triazolo(4,3-a)quinoxaline-4-one
    • 1-Oxo-5-methyl-8-carboxy-1 H,4H(1,2,4)triazolo(4,3-a)quinoxalin-4-one
    Example 4 1-Oxo-5-methyl-1 H,4H(1,2,4)triazolo(4,3-a)quinoxalin-4-one
  • 15 g. of the product of Paragraph C, Example 3 was added with stirring to Dowtherm A (200 ml.) at 230°C. The reaction mixture was kept at this temperature until cyclization was completed (usually less than 20 minutes at this or higher temperature).
  • Upon completion of cyclization, the reaction mixture was cooled, filtered, and the solid washed well with ethanol and methylene dichloride.
    • Example 5 1-Oxo-2-acetyl-5-methyl-1 H,4H(1,2,4)triazolo(4,3-a)quinoxalin-4-one
  • A mixture of 2.16 g. (.01 mol) of the product of Paragraph D, Example 3, 30 ml. of pyridine and 30 ml. of acetic anhydride was refluxed for 1 hour, the solvent was evaporated and the residue recrystallized from acetonitrile, m.p. 288-289°C.
    • Example 6 Potassium-1-oxo-5-methyl-1 H,4H(1,2,4)triazolo(4,3-a)quinoxalin-4-one-8-carboxylate
  • A mixture of 2.0 g of 1-oxo-5-methyl-8-carbomethoxy-1 H,4H(1,2,4)triazolo(4,3-a)quinoxalin-4- one, 250 ml. of ethanol and 1 g. of potassium hydroxide was refluxed for 2 hours. The acid dissolved to give a clear solution, then a precipitate formed which was filtered, washed with alcohol and dried, m.p. 300°C.
  • Other compounds of formula II prepared according to the processes described above include
    Figure imgb0009
  • The compounds of this invention are useful anti-allergic agents. Exemplary of the present new compounds is 6-methylpyrido(2,3-e)(1,2,4)triazolo(4,3-a)pyrazine-1,4-(2H,5H)dione which reduced wheal formation by 53% at 25 mg./kg. (p.o.) when screened according to the Rat Passive Cutaneous Anaphylaxis Screen as described by I. Mota, Life Sciences, 7, 465 (1963) and Z. Ovary, et al., Proceedings of Society of Experimental Biology and Medicine, 81, 584 (1952). In addition, the said compound showed an I50 of 9.0 µM in inhibition of histamine release from passively sensitized rat mast cells according to the procedure described by E. Kusner, et al., Journal of Pharmacology by Experimental Therapeutics.

Claims (21)

1. An anti-allergic compound of the formulae:
Figure imgb0010
wherein
X is S or O; each of R1 and R2 is hydrogen, C1―C10 alkyl, C2―C10 alkenyl, C2―C10 alkynyl, cyclo C3―C10 alkyl, C6―C10 aryl, C6―C10 ar C1―C10 alkyl, sulfonamido, halogen, C1―C10 alkoxy, C2―C10 alkenyloxy, C2―C10 alkynyloxy, cyano, hydroxy, nitro, amino, C1―C10 alkylamino, C1―C10 alkanoylamino, carb C1―C10 alkoxyamino, methanesulfonyl, carboxy, carb C1―C10 alkoxy, trihalomethyl, or taken together, methylenedioxy;
each of R3 and R4 is hydrogen, C1―C10 alkyl, C6―C10 aryl, C2-5-alkanoyl, benzoyl, C6―C10 ar C1―C10 alkyl, cyclo C3―C10 alkyl, cyclo C3―C10 alkyl CH2―, or carb C1―C10 alkoxy;

and the acid addition salts thereof.
2. An anti-allergic compound according to claim 1 of the formula:
Figure imgb0011
wherein
each of R1 and R2 is hydrogen, C1―C10 alkyl, C2―C10 alkenyl, C2―C10 alkynyl, cyclo C3―C10 alkyl, C6―C10 aryl, C6―C10 ar C1―C10 alkyl, sulfonamido, halogen, C1―C10 alkoxy, C2―C10 alkenyloxy, C2―C10 alkynyloxy, cyano, hydroxy, nitro, amino, C1―C10 alkylamino, C1―C10 alkanoylamino, carb C1―C10 alkoxyamino, methanesulfonyl, carboxy, carb C1―C10 alkoxy, trihalomethyl, or taken together, methylenedioxy; and
each of R3 and R4 is hydrogen, C1―C10 alkyl, C6―C10 aryl, C2-5 alkanoyl, benzoyl, C6―C10 ar C1―C10 alkyl, cyclo C3―C10 alkyl, cyclo C3―C10 alkyl CH2―, or carb C1―C10 alkoxy;

and acid addition salts thereof.
3. 5-Methyl-pyrido-[2,3-e]-[1,2,4]-triazolo[4,3-a]-pyrazine-1,4-[2H,5H]-dione.
4. 2-Acetyl-5-methyl-pyrido[2,3-e]-[1,2,4]-triazolo-[4,3-a]-pyrazine-1,4-[2H,5H]-dione.
5. 5-Methyl-benzo[g]-[1,2,4]-triazolo[4,3-a]-quinoxaline-1,4-[2H,5H]-dione.
6. A therapeutical composition comprising a compound according to claim 1.
7. An anti-allergic compound according to claim 1 or the formula:
Figure imgb0012
wherein,
each of R1 and R2 is hydrogen, C1―C10 alkyl, C2―C10 alkenyl, C2―C10 alkenyl, cyclo C3―C10 alkyl, C6―C10 aryl, C6―C10 ar C1―C10 alkyl, sulfonamido, halogen, C1―C10 alkoxy, C2―C10 alkenyloxy, C2―C10 alkynyloxy, cyano, hydroxy, nitro, amino C1―C10 alkylamino, C1―C10 alkanoylamino, carb C1―C10 alkoxyamino, methanesulfonyl, carboxy, carb C1―C10 alkoxy, trihalomethyl, or taken together, methylenedibxy; and
each of R3 and R4 is hydrogen, C1―C10 alkyl, C6―C10 aryl, C2-5 alkanoyl, benzoyl, C6―C10 ar C1―C10 alkyl, cyclo C3―C10 alkyl, cylco C3―C10 alkyl CH2―, or carb C1―C10 alkoxy;

and acid addition salts thereof.
8. A compound according to claim 7, wherein R, and R2 are hydrogen.
9. A compound according to claim 7 wherein R3 is methyl.
10. A compound according to claim 9, wherein R4 is hydrogen.
11. A compound according to claim 9, wherein R4 is acetyl.
12. A compound according to claim 7, wherein R, is hydrogen, R2 is 8-trifluoromethyl, R3 is methyl and R4 is hydrogen.
13. A compound according to claim 7, wherein R, is hydrogen, R2 is hydrogen, R3 is methyl and R4 is hydrogen.
14. A compound according to claim 7, wherein R1, R2, R3, and R4 are hydrogen.
15. A compound according to claim 7, wherein R1 is hydrogen, R2 is 8-chlorine, R3 is methyl, and R4 is hydrogen.
16. A compound according to claim 7, wherein R, is hydrogen, R2 is hydrogen, R3 is methyl, and R4 is carbethoxy.
17. A compound according to claim 7, wherein R, is hydrogen, R2 is 8-carbomethoxy, R3 is methyl, and R4 is hydrogen.
18. A compound according to claim 7, wherein R1 is hydrogen, R2 is 6-methyl, R3 is methyl, and R4 is hydrogen.
19. A compound according to claim 7, wherein R, is 7-chlorine, R2 is hydrogen, R3 is n-propyl, and R4 is hydrogen.
20. A compound according to claim 7, wherein R1, R2 and R4 are each hydrogen and R3 is n-propyl.
21. A compound according to claim 7, wherein R1 is 7-chloro, R2 and R4 are hydrogen, and R3 is methyl.
EP81103498A 1980-05-09 1981-05-07 Triazaloquinoxalin-1,4-diones Expired EP0039920B1 (en)

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